JPH02169569A - Drug containing cyclic amine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [J is phenyl, pyridyl, indanyl, indanonyl, alkyl, etc.; B is group of formula II-formula V (R<2> is H or methyl; R<3> is H, alkyl, acyl, phenyl, etc.; R<4> is H, alkyl or phenyl; n is 0-10), etc.; T is N or C; Q is N, C or N-O; K is H, phenyl, arylalkyl, cinnamyl, alkyl, pyridylmethyl, acyl, etc.; q is 1-3] and its salt. EXAMPLE:1-Benzyl-4-[2-[(1-indanon)-2-yl]]ethylpiperidine hydrochloride. USE:It has strong acetylcholine esterase inhibiting action and choline acetyltransferase activating action and is useful for the remedy and prevention of central nervous diseases. PREPARATION:A compound of formula I wherein B is group of formula V can be produced e.g. by reacting an acid halide of formula VI with a cyclic amine derivative of formula VII in an organic solvent in the presence of a desalting agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a medicament containing a novel cyclic amine derivative as an active ingredient.

[Background leading to the invention and prior art]

With the aging population rapidly increasing, there is a strong desire to establish a treatment for senile dementia such as Alzheimer's type senile dementia.

However, although various attempts have been made to treat senile dementia with drugs, there are currently no drugs that are fundamentally effective against these diseases.

The development of therapeutic drugs for these diseases is being researched from various directions, but a promising direction is the use of acetylcholine precursors and acetylcholinesterase inhibitors, since Alzheimer's type senile dementia is accompanied by a decline in brain cholinergic function. It has been proposed and actually attempted to develop from this direction. Typical anticholinesterase inhibitors include physostigmine and tetrahydroaminoacridine, but these drugs have drawbacks such as insufficient efficacy and undesirable side effects, so they are not definitive therapeutic agents. The current situation is that there is no such thing.

Furthermore, recently choline acetyltransferase (ChA
T) It has been noticed that the activation effect is also effective in treating these diseases.

Therefore, the present inventors have conducted extensive research over many years on compounds that have this effect.

As a result, it has been found that a cyclic amine derivative represented by the general formula (1) described later can achieve the intended purpose.

Specifically, the compound of the present invention represented by the following structural formula (I) is an excellent choline acetyltransferase (ChA
T) It has an activating effect and also has strong and highly selective anti-acetylcholinesterase activity, so it increases the amount of acetylcholine in the brain, is effective in memory disorder models, and has been widely used in this field. Compared to physostigmine, it has the major characteristics of a longer duration of action and higher safety, and the value of the present invention is extremely high.

The compounds of the present invention were discovered based on their activating action on choline acetyltransferase, and are therefore useful for the treatment and treatment of various diseases caused by central cholinergic function, that is, in vivo deficiency of acetylcholine as a neurotransmitter. Effective for prevention.

Typical examples include various types of dementia such as Alzheimer's type senile dementia, but others include Huntington's chorea, Pick's disease, and tardive dyskinesia.

Therefore, the objects of the present invention are to provide a novel cyclic amine derivative that is effective as a medicine, particularly for the treatment and prevention of diseases of the central nervous system, to provide a method for producing this novel cyclic amine derivative, and to use it as an active ingredient. The aim is to provide medicines that

[Structure and effects of the invention]

The target compound of the present invention is a cyclic amine derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[In the formula, J is (a) a substituted or unsubstituted group shown below; ■ phenyl group, ■ pyridyl group, ■ biradyl group, ■ quinolyl group, ■
cyclohexyl group, ■ quinoxalyl group or ■ furyl group, etc. A monovalent or divalent group selected from the following group optionally substituted with phenyl group; ■ indanyl, ■ indenonyl, ■ indenyl, ■ indenonyl, ■ indanedionyl, ■tetralonyl, ■penzusuberonyl, ■indanolyl, 0 formula (C) a monovalent group derived from a cyclic amide compound, (6) lower alkyl group, or (e) formula R'-CH=CH- (in the formula , R1 means a hydrogen atom or a lower alkoxycarbonyl group).

atom, lower alkyl group, acyl group, lower alkylsulfonyl group, optionally substituted phenyl group or benzyl group), formula -Cl (=CH-(C)
I) Group represented by n-, formula -〇-C-0- (CH)
,.

R" A group represented by R", a group represented by the formula -〇-C-NH-(C)ri, -, a group represented by the formula -NH-C-(CH), -,
A group represented by the formula -CH2-CO-NH-(CH) h-R2R2, a group represented by the formula -(CH2)2-CD-NH-(C
A group represented by the formula -CH-(C)l), , -, a group represented by the formula -CH-(C)l), , -
A group represented by the above formula, a group represented by the formula -C-CI(=CH-C)12-, a group represented by the formula, a group represented by the formula -CH=Cfl-C-N
A group represented by H-(CH2) 2-, a group represented by the formula -NH-, a group represented by the formula -8-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group means.

T means a nitrogen atom or a carbon atom.

ゝ＼、 O is a nitrogen atom, a carbon atom, or 2 N-0/ means the group shown.

is a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group which may be substituted with a phenyl group, a cinnamyl group which may be substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane group. It means a methyl group, furylmethyl group, cycloalkyl group, lower alkoxycarbonyl group or acyl group.

q means an integer from 1 to 3.

In the formula, == means a single bond or a double bond. ] In the above definition of the compound (I) of the present invention, J,
The lower alkyl groups found in K, R', and R' are
A straight or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group: 5ec-butyl group, tert
-Butyl group, pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group group, 2-methylpentyl group, 3-methylpentyl group, 1.1-dimethylbutyl group, 1,2-dimethylbutyl group, 2.2-dimethylbutyl group, 1.3-dimethylbutyl group, 2,3- Dimethylbutyl group, 3.3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1
．． 1.2-) dimethylpropyl group, 1.2.2-)
IJ means methylpuzolol group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc.

Among these, preferable groups include methyl group, ethyl group, propyl group, isopropyl group, and the most preferable group is methyl group.

"Substituted or unsubstituted groups shown below in J; ■ phenyl group, ■ pyridyl group, ■ pyrazyl group, ■ quinolyl group,
In the definition of "■ cyclohexyl group, ■ quinoxalyl group, or Number 1
-6 lower alkyl group; lower alkoxy group corresponding to the above lower alkyl group such as methoxy group, ethoxy group: nitro group; halogen such as chlorine, bromine, fluorine: carboxyl group; methoxycarbonyl group, ethoxycarbonyl group,
Lower alkoxycarbonyl groups corresponding to the above lower alkoxy groups such as isopropoxycarbonyl group, n-propoxycarbonyl group, n-butyroxycarbonyl group; amino group; mono-lower alkylamino group; di-lower alkylamino group; carbamoyl group; Acylamino groups derived from aliphatic saturated monocarboxylic acids having 1 to 6 carbon atoms, such as acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, pivaloylamino group, dichlorohexyloxycarbonyl group, etc. Cycloalkyloxycarbonyl group: lower alkylaminocarbonyl group such as methidicarbonyl group, ethylaminocarbonyl group; corresponds to the lower alkyl group defined above such as methylcarbonyloxy group, ethylcarbonyloxy group, n-propylcarbonyloxy group lower alkylcarbonyloxy group; halogenated lower alkyl group represented by trifluoromethyl group; hydroxyl group; formyl group; ethoxymethyl group, methoxymethyl group,
Examples include lower alkoxy lower alkyl groups such as methoxyethyl group. In the explanation of the substituents above, "lower alkyl group" and "lower alkoxy group" refer to
It is intended to include all groups derived from the above definitions. The substituents may be substituted with the same group or with 1 to 3 different groups.

Furthermore, in the case of a phenyl group, the following cases are also included in the substituted phenyl group. (wherein, G is a group represented by the formula -〇-, a group represented by the formula -〇-C-, a group represented by the formula -0-
A group represented by the formula -CH, -NH-C-,
It means a group represented by the formula -CH, -0-, a group represented by the formula CH2-3O□-, a group H ↑ represented by the formula -CH-, or a group represented by the formula -CH2-3-. E means a carbon atom or a nitrogen atom.

Among these, preferred substituents for the phenyl group are:
Substituents include lower alkyl groups, lower alkoxy groups, nitro groups, halogenated lower alkyl groups, lower alkoxycarbonyl groups, formyl groups, hydroxyl groups, lower alkoxy lower alkyl groups, halogens, benzoyl groups, benzylsulfonyl groups, etc. may be the same or different and may be two or more.

Preferred groups for the pyridyl group include lower alkyl groups, amino groups, and halogen atoms.

Preferred examples of the pyrazyl group include a lower alkoxycarbonyl group, a carboxyl group, an acylamino group, a carbamoyl group, and a cycloalkyloxycarbonyl group.

In addition, the pyridyl group as J is a 2-pyridyl group, a 3-pyridyl group,
A pyridyl group or a 4-pyridyl group is preferable, a pyrazyl group is preferably a 2-pyrazyl group, a quinolyl group is preferably a 2-quinolyl group or a 3-quinolyl group, a quinoxalyl group is preferably a 2-quinoxalyl group or a 3-quinoxalyl group, The furyl group is preferably a 2-furyl group.

In the definition of J, ■ ~ described in group ra)
Regarding ■, it is as follows.

To give a representative example, in the series of formulas shown below, t means 0 or an integer from 1 to 4, S is one of the same or different substituents in the definition of J (a) above, or hydrogen It means an atom, preferably a hydrogen atom (unsubstituted), a lower alkyl group, or a lower alkoxy group. Furthermore, adjacent carbon atoms of the phenyl ring may be substituted with an alkylenedioxy group such as a methylenedioxy group or an ethylenedioxy group.

Among these, the most preferred case is unsubstituted or substituted with 1 to 3 methoxy groups.

Note that the above indanolidenyl is an example of a divalent group in which the phenyl group in the definition of J(b) may be substituted. That is, it is a typical divalent group derived from indanonyl in J(b).

In the definition of J, the monovalent group derived from a cyclic amide compound includes, for example, quinazolone, tetrahydroisoquinolinone, tetrahydrobenzodiazepinone, hexano\hydropenzazocinone, etc. It is sufficient that a cyclic amide exists in the structural formula, and the present invention is not limited to these. Although there may be cyclic amides derived from a single ring or a fused heterocycle, the fused heterocycle is preferably a fused heterocycle with a phenyl ring. In this case, the phenyl ring may be substituted with a lower alkyl group having 1 to 6 carbon atoms, preferably a methyl group, a lower alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group, or a norogen atom.

Preferred examples are as follows.

■ (a) (b) (c) (d) axis) (h) (j) (k) (+) (m) (n) In the above formula, Y in formula (i) and (1) is It means a hydrogen atom or a lower alkyl group, and V in the formula (k) is a hydrogen atom or a lower alkoxy group, and the formula (m).

%1 in (n). W2 means a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and W3 means a hydrogen atom or a lower alkyl group.

Note that in formulas (j) and (1), the ring on the right is a 7-membered ring, and in formula (k), the ring on the right is an 8-membered ring.

Among the above definitions of J, the most preferred are a monovalent group derived from indanone, in which the phenyl ring may be substituted, and a monovalent group derived from a cyclic amide compound.

In the definition of B, the group represented by the formula -(CH), - is
When R2 is a hydrogen atom, it is represented by the formula -(CH2), -, and it means that one or more methyl groups may be bonded to any carbon atom of the alkylene chain. In this case, preferably n is 1-3.

Furthermore, in the series of groups B, a case where the base circle has an amide group is also one of the preferable groups.

A more preferable group is the formula = (CH-CH=CH)
A group represented by b- (in the formula, b means an integer of 1 to 3), a group represented by the formula =CH-(CH2) c- (in the formula, C means 0 or an integer of 1 to 9) group, formula = (CH
-CH) d= (in the formula, d means 0 or an integer of 1 to 5), a group represented by the formula -NH-, a group represented by the formula -〇-, or a group represented by the formula -8- The groups shown can be mentioned.

However, particularly preferred rings are those of the formula.

"Substituted or unsubstituted phenyl group" in the definition of K, "
In “substituted or unsubstituted arylalkyl group”,
The substituents are the same as those defined in (a) (1) to (2) in the definition of J above.

The arylalkyl group means a benzyl group, phenethyl group, etc. in which the phenyl ring is substituted with the above substituent or is unsubstituted.

Specific examples of the pyridylmethyl group include 2-pyridylmethyl group, 3-pyridylmethyl group, and 4-pyridylmethyl group.

Regarding K, most preferred are an arylalkyl group which may have a phenyl group substituted, a substituted or unsubstituted phenyl group, and a cinnamyl group which may have a phenyl group substituted.

Preferred arylalkyl groups are specifically, for example, benzyl groups and phenethyl groups, in which the phenyl group is substituted with a lower alkoxy group having 1 to 6 carbon atoms, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, etc. You can leave it there.

- means a single bond or a double bond.

An example of a double bond is a case where the above-mentioned phenyl ring is a divalent group derived from an optionally substituted indanone, that is, an indanolidenyl group.

In the present invention, pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, phosphate, formate, acetate, trifluoroacetate, maleate, Organic acid salts such as tartrate, methanesulfonate, benzenesulfonate, and toluenesulfonate can be mentioned.

Depending on the selection of substituents, for example, alkali metal salts such as IJium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexyl Amine salts, organic amine salts such as N,N'-dibenzylethylenediamine salts, ammonium salts, etc. may be formed.

Note that the compounds of the present invention may have asymmetric carbon atoms depending on the type of substituents and optical isomers may exist, but it goes without saying that these belong to the scope of the present invention.

To give one specific example, when J has an indanone skeleton, since it has an asymmetric carbon, geometric isomers, optical isomers, diastereomers, etc. may exist, but all are included in the scope of the present invention. It will be done.

Taking all these definitions into account, particularly preferred compound groups are as follows.

[In the formula, J' is a monovalent or divalent group selected from the following group, which may be substituted with a phenyl group: ■ indanyl, ■
indanoninohe ■indenyl, ■indenonyl, ■indandioninope ■tetralonyl, ■penzusuberonil,
■Injury.

B, T, Q, q, K have the same meanings as above. ] or a pharmacologically acceptable salt.

In the above definition of Jl, the most preferable groups include an indanonyl group, an indanedionyl group, and an indanedionyl group in which the phenyl group may be substituted. Also, in this case, the phenyl group is unsubstituted or
Most preferably, it is substituted with the same or different ykM group, halogen, or lower alkoxy group. The lower alkoxy group refers to a group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an inpropoxy group, an n-propoxy group, an n-butoxy group, and can be substituted with 1 to 4 substitutions, but it is often 2 substitutions. preferable. The most preferred case is that the methoxy group is disubstituted.

(A> Among the compounds included in the formula, a more preferable group of compounds is the compound (8) represented by the following general formula.

[In the formula, Jl is a monovalent or divalent group selected from the following group which may be substituted with a phenyl group;
Indanoninope■indenyl, ■inf'/ninohe■indandiionyl, ■tetralonyl, ■penzusuberonyl, ■ingen.

B1 has the formula -(CH), -(wherein n is 0 or 1 to 10
means an integer of R2 means a hydrogen atom or a methyl group in such a form that the alkylene group represented by the formula -(CH)n- has no substituents or has one or more methyl groups. ), a group represented by the formula =(CH-CH
=CH)h- (in the formula, b means an integer of 1 to 3);
means 0 or an integer from 1 to 9) or a group represented by the formula = (CH-CH) d= (wherein d means 0 or an integer from 1 to 5) .

T, Q, q, K have the same meanings as above. ]
Among the compounds included in formula (B), a more preferable group of compounds includes compound (C) represented by the following general formula.

(In the formula, J', B', and K have the same meanings as above.)

Among the compounds included in formula (C), a more preferable group of compounds includes compound (D) represented by the following general formula.

K1 means a substituted or unsubstituted phenyl group, an optionally substituted arylalkyl group, or an optionally substituted cinnamyl group.

B1 has the same meaning as above. ) There are various possible methods for producing the compound of the present invention, but typical methods are as follows.

Manufacturing method Δ OR' [-In formula (1), B is the formula -C-N-(C1l)
,.

(In the formula, n, R2, R4 have the above meanings)] (In the formula, J2 is a group selected from indanonyl, indanedionyl, and indanedionyl group, which may be substituted with a phenyl group) means.

(In the formula, J, R', R", n, T, Q, q
, K has the above meaning and Hal means a halogen atom. ) That is, an acid halide represented by general formula (Il) and a cyclic amine derivative represented by °-general formula III) are combined, for example, with sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride. , in an organic solvent such as chloroform, benzene, toluene, dioxane, tetrahydrofuran, dimethylformamide (DMF), in the presence of a desalting agent such as triethylamine,
Compound (TV), which is one of the target substances, can be easily obtained by reacting with water cooling, room temperature, or heating.

Manufacturing method B J is quinazolone, tetrahydroisoquinolin-one,
When it is a monovalent group derived from a cyclic amide compound selected from tetrahydrobenzodiazepin-one and hexahydropenzazocin-one, it can also be produced by the following method.

((CH2),,' [wherein, R8 and R8 are hydrogen atoms, lower alkyl groups, lower alkoxy groups, and halogen atoms, p is an integer of 1 to 3, and Z is represented by the formula -CH2- group or formula -N-
(In the formula, R1 represents a hydrogen atom or a lower alkyl group.)

Hal, R2,n, T, Q, q, K have the meanings given above. ] That is, the substitution represented by general formula (V) -
1,2,3°4-tetrahydro-5H-1-penzazepin-2-one is condensed with a compound represented by general formula (VI) in, for example, a dimethylformamide solvent in the presence of, for example, sodium hydride. One of the target substances, (■), can be obtained.

and B is -(C)I)n If the group is shown as It can also be manufactured by the manufacturing method.

That is, 2-hydroxymethylnicotinic acid lactone (■
) and a compound represented by general formula (IX) can be reacted by a conventional method to obtain a compound represented by general formula (X), which is one of the target substances. The reaction temperature is 200
Preferably around ℃.

The manufacturing method (R' and R9 have the same meanings as defined above for R5 and R6; n and R2 have the same meanings as above) can also be produced by the following manufacturing method.

That is, substituted 2,3-dihydroxypyrrolo(3,4-b)benzene represented by general formula (X[) and general formula (V
One of the target substances, compound (X), is reacted with the compound represented by
I[) can be obtained.

In some cases, it can also be manufactured using the following manufacturing method.

Can be done.

In general formula (1), J is an optionally substituted phenyl group, B is a group represented by the formula -C-(CH2), -,
Alternatively, when H is a group represented by the formula -CCH2-CH[:R2-, it can also be produced by the following method. In the following formula, RIG means the substituent in the definition of J (a) above.

That is, 2,3-viradylcarboxylic anhydride (■) is added to, for example, isopropyl alcohol and refluxed. After distilling off the alcohol, the compound represented by the general formula (IX) is reacted with a compound represented by the general formula (IX) in a solvent such as tetrahydrofuran to obtain a compound (Xf/), which is one of the target substances.■ Tetralonyl, ■ Penzusuberonyl. Or Formula 0, for example, in a solution such as tetrahydrofuran, diisopropylamine and n-butyllithium/hexane solution are added, and at a temperature of about -80°C, acetophenone represented by general formula (XV) and general formula ( The compound (XVII) is obtained by condensation with a compound represented by X'W). This is dehydrated in a solvent such as toluene in the presence of, for example, p-)luenesulfonic acid, and then catalytically reduced by a conventional method to obtain a compound (expletive) which is one of the target substances.

Production method G In the present invention, among those defined in (J), phenyl group may be substituted ■indanyl, ■indanonyl, ■indanionyl, = (Cfl-CH:CH
) b- (in the formula, b means an integer of 1 to 3), a group represented by the formula -CH-(CH2) c- (in the formula, C means 0 or an integer of 1 to 9); The group or formula shown =
When it is a group represented by (CH-CH) d= (in the formula, d means 0 or an integer of 1 to 5), it can be produced, for example, by the following two methods.

(In the formula, Jl indicates the case where J has the above definition, and B1
means a residue excluding the group bonded to the leftmost carbon atom in the above definition of 8. 〉That is, general formula (m)
A phosphonate represented by is reacted with an aldehyde compound represented by general formula (■) (Wittig reaction) to obtain a compound represented by general formula (m), which is one of the target substances, and then this is contacted with Compound (■■), which is one of the target substances, can be obtained by reduction.

Catalysts for carrying out the Wittig reaction include, for example, sodium methylate (MeONa), sodium ethylate (EtONa), t-BuOK, Nat(
etc. can be mentioned. In this case, examples of the solvent include tetrahydrofuran (THF), dimethylformamide (DMF), ether, nitromethane, dimethyl sulfoxide (DMSO), etc. Preferably, the reaction temperature is from room temperature to about 100°C.

When carrying out catalytic reduction, it is preferable to use, for example, palladium on carbon, Raney nickel perodium on carbon, etc. as a catalyst.

(S).

Specific cases where it is a group are as follows.

(S).

+ group (in the formula, R1+, 1712 is the same - among the definitions of S)
or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, or halogens), B is the formula -
(CH2) is a group represented by n- (in the formula, n means a group represented by 1 to 6), and is represented by the formula (in the formula, n13.R has the same definition as RIJI2). The following are specific cases where the group is a group.

I2+ That is, a compound such as a substituted or unsubstituted indanone represented by the formula (nI [ A compound represented by the general formula (I) is obtained.

In this reaction, lithium diisobutyramide is produced by a solution of diisopropylamine and n-butylhexane in a solvent such as tetrahydrofuran, preferably at a temperature of about -80°C. Add the compound. Next, the aldehyde represented by the general formula (XX) is added and reacted by a conventional method, and the mixture is dehydrated by raising the temperature to room temperature to obtain the enone compound represented by the general formula (XXI).

Another method for this reaction is to dissolve both ((■■) and (XX) in a solvent such as tetrahydrofuran, add a base such as sodium methylate at about 0°C, and react at room temperature. It can also be produced by a method.

A compound represented by formula (XXII) can be obtained by reducing the enone compound obtained by the above production method in the same manner as shown above.

The following are specific cases in which this is the case.

8 is a group represented by the formula =(CH2), -, and the formula (S).

Similarly to that described in manufacturing method 1, It is shown as follows.

One Specific Example: Manufacturing Method H When J is an indanolyl group in which the phenyl group portion may be substituted, it can be manufactured by the following method.

That is, compound (XXIV), which is one of the target substances, can be obtained by reducing compound (■■) with, for example, boron hydride at 0° C. to room temperature. The solvent in this case is preferably methanol, for example.

When J represents an indenyl group in which the phenyl group may be substituted, it can also be produced by the following method.

That is, compound (XXl'V) is dehydrated in the presence of hydrochloric acid or the like by a conventional method to obtain compound (XXV), which is one of the target substances.
) can be obtained.

Production method J When J indicates an indenonyl group in which the phenyl group may be substituted, it can also be produced by the following method.

That is, an indanone compound represented by the formula (■■),
For example, in a solvent such as carbon tetrachloride, N-bromosuccinimide (NBS) and benzoyl peroxide are heated under reflux to form bromination, and then this bromine compound (registered) is brominated in a solvent such as tetrahydrofuran with 1,8 β-dissociation is carried out by heating under reflux with -diazabicyclo[5°4.0]undec-7-ene (DBU) to obtain an indanone compound (■■). Note that the above-mentioned bromine compound can also be reacted with other halogens.

In addition, in the production method GJ, indanones used as starting materials are commercially available products or produced by the following method.

On the other hand, aldehydes such as 5OC12 can be produced, for example, by the following method.

Or specific example 1 That is, as mentioned above, using the compound represented by formula (i) or formula (ii) as a starting material, converting it into an aldehyde form by the above method, repeating the Wittig reaction shown below, or combining it. The target starting material can be obtained by carrying out a carbon enrichment reaction.

As the Wittig reagent, for example, methoxymethylenetriphenylphosphorane is used when increasing by one carbon, and formylmethylenetriphenylphosphorane is used when increasing by two carbons.

Methoxymethylenetriphenylphosphorane is produced from methoxymethylenetriphenylphosphonium chloride and n-butyllithium, for example in ether or tetrahydrofuran. After adding a ketone body or an aldehyde body to this to form a methoxyvinyl body, an aldehyde can be synthesized by acid treatment.

Specific examples for specific cases are shown below.

On the other hand, when using formylmethylenetriphenylphosphorane, it can be synthesized by adding a Wittig reagent to a solution of a ketone or aldehyde as a raw material in ether, tetrahydrofuran, or benzene, and heating to reflux from room temperature.

The unsaturated aldehyde synthesized in this manner can be catalytically reduced to a saturated aldehyde, if necessary. As the catalyst in this case, palladium on carbon, Raney nickel, rhodium on carbon, etc. are preferable.

The compounds of general formula (I) and acid addition salts thereof obtained as described above are useful for the treatment of various senile dementias, particularly senile dementia of the Alzheimer type.

In order to demonstrate the usefulness of the compound represented by general formula (I) and its acid addition salt, pharmacological test results will be explained below.

Experimental Example 1 Using mouse brain homogenate as an acetylcholinesterase source, esterase activity was measured according to method 1) of Illillman et al. Acetylthiocholine, analyte and DT as substrates in mouse brain homogenate.
After adding NB and incubation, the produced thiocholine interacts with DTNB, and the resulting yellow product is detected at 412 nm.
The acetylcholinesterase activity was determined by measuring the change in absorbance at .

The acetylcholinesterase inhibitory activity of the sample was expressed as 50% inhibitory concentration (Icso).

The results are shown in Table 1.

1) Ellman, G.L., Courtney
, K.D., ,Andres, V.

and Featherstone, R, M, (
1961) Biochem, Pharmacol
,.

7.88-95 Table 1 Table 1 (Continued Peeling Experiment Example 2 EX vivo Acetylcholinesterase Inhibition Effect) The test substance was orally administered to rats, and one hour later, cerebral hemispheres were collected, and after homogenization, acetylcholinesterase activity was measured. Note that the physiological saline administration group was used as a control.

The results are shown in Table 2.

Table 2 Experimental Example 3 Effect of scopolamine on passive avoidance learning disorder 1Wis
Using tar male rats, the apparatus was 5 steps.
A through-type light/dark box was used. The specimen was administered orally 1 hour before the trial, and 0.5 mg of scopolamine was administered 30 minutes before the trial.
/kg (ip) was treated. In training trials, animals were placed in a lighted room, and immediately after entering the darkened room, the guillotine door was closed and an electric shock was administered through a grid on the floor. After 6 hours, the animals were placed in the light room again as a retention trial, and the time until they entered the dark room was measured and evaluated.

The effect is calculated based on the difference in reaction time between the saline administration group and the scopolamine administration group as 100%, and the percentage of reversal depending on the sample (Rever).
se%).

Book I Z, Bokolanecky & Jar
vik::nt, J, Neuropharmaco16
, 217-222 (1967) The results are shown in Table 3.

Table Experimental Example 4 Measurement of choline acetyltransferase (ChAT) activation activity Measurement of activity Rat fetal brain neurons were cultured according to the method of Heft11) et al. A 17-day old female Wistar rat fetal cerebral hemisphere was treated with trypsin. 2x number of cells
10' pieces 10.5 mj! At the same time, test compounds were added, transferred to a microplate, and incubated at 37°C, 5% CO□
-95% 02 for 7 days. The chAT activity of the cultured neurons in the microplate was measured according to the method of Fonnum.

“C-Acety! Coenzym” for nerve cell culture medium
e Add A and react for 1 hour to produce "C-AC"
Etyl-choline was extracted with toluene in the presence of tetraphenylboron, and measured using a liquid scintillation counter to determine ChAT activity. ChAT of sample
The activation effect was expressed as control %.

The results are shown in Table 4.

1) F, Heft1. J, Haytikka;
F, Eekenestein.

H, Gnahn, R, Heuman and M, S
chwab, Neuro-science, 14
．． 55-68 (1985) 2) F, Fonnum
: J. Neurochem, 24. 407
-409 Table 4 From the above pharmacological experiment examples, it was revealed that it has a strong acetylcholinesterase inhibitory effect and choline acetyltransferase activating effect.

Among the compounds (1) of the present invention, compounds in which J is a group derived from indanone, the phenyl ring of which may be optionally substituted, are most preferred. That is, in particular, the compound in which J is a group derived from indanone in which the phenyl ring may be optionally substituted has a structure that is significantly different from that of conventional acetylcholinesterase inhibitors, and has excellent choline acetyltransferase activation. It has a strong acetylcholinesterase inhibitory effect, has a large main action and side effects, has a long duration of action, is highly water-soluble, and is an extremely stable compound, which is advantageous in terms of formulation. It has excellent bioavailability and is the first
It has characteristics such as being less susceptible to pass effects and having good intracerebral transferability.

Therefore, an object of the present invention is to provide a novel pharmaceutical agent containing as an active ingredient a compound effective for treating various dementias and sequelae of cerebrovascular disorders based on choline acetyltransferase activation activity.

In addition, when a toxicity test was conducted on rats for a representative compound of the present invention (compound Nα4.13.15.19.79 in Table 3 above), approximately 100 mg of each compound was conducted.
No serious toxicity was observed at doses greater than /kg. The compounds of the present invention are effective for all diseases for which choline acetyltransferase activation is effective. Typical diseases include various types of senile dementia; especially Alzheimer's type senile dementia;
Cerebrovascular disorders associated with stroke (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, head trauma, etc.: After-effects of encephalitis, decreased attention span associated with cerebral palsy, etc., speech disorders, decreased motivation, emotional disorders, memorization disorders, Treatment, prevention, and remission of hallucinations, delusional states, behavioral abnormalities, etc.
Effective for improvement, etc.

The effectiveness of the choline acetyltransferase-activating effect of the compounds of the present invention on these diseases is thought to be due to the fact that the amount of acetylcholine in the brain is increased by the above-mentioned effect.

Furthermore, since the compounds of the present invention have strong and highly selective anticholinesterase actions, they are also useful as medicines based on these actions.

That is, in addition to Alzheimer's type senile dementia, it is also useful for, for example, Huntington's chorea, Pick's disease, late-onset disorder, and the like.

When the compound of the present invention is used as these medicines, it is administered orally or parenterally, but it is usually administered parenterally, such as by intravenous, subcutaneous, or intramuscular injections, herbal medicines, or sublingual tablets. Ru. Dosage 4: Level of symptoms; patient age, sex, weight, sensitivity differences; administration method;
It varies depending on the timing and interval of administration, the nature, preparation, type of pharmaceutical preparation; the type of active ingredient, etc., but is not particularly limited,
The amount is usually about 0.1 to 300 mg per day for adults, preferably about 1 to 100 mg, and this is usually administered in 1 to 4 divided doses per day.

In order to formulate a compound of the present invention, it is prepared into a dosage form such as an injection, a herbal medicine, a sublingual tablet, a tablet, or a capsule by a conventional method in the field of pharmaceutical preparation.

When preparing injections, add p)l adjusters, buffers, suspending agents, solubilizing agents, stabilizers, tonicity agents, preservatives, etc. to the herbal medicine as necessary, and prepare in a conventional manner. Administer as intravenous, subcutaneous, or intramuscular injection. At that time, if necessary, it is also possible to freeze-dry it by a conventional method.

Examples of suspending agents include methyl cellulose, polysorbate 80, hydroxyethyl cellulose,
Examples include gum arabic, powdered tragacanth, sodium carboxymethyl cellulose, and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, magrogol, and castor oil fatty acid ethyl ester.

Examples of stabilizers include sodium sulfite, sodium metasulfite, and ether; examples of preservatives include methyl parahydroxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. .

[Examples] The present invention will be described in more detail below with reference to Examples, but it goes without saying that the technical scope of the present invention is not limited to the scope of these Examples.

In addition, in the following examples, all NMR values show values measured in one piece.

1-benzyl-4-(2-[: (1-indanone)-
0.37 g of 2-ylidenyl]]ethylpiperidine was dissolved in 1Qml of methanol, and 5% rhodium-carbon 0.1
g was added. After hydrogenation at room temperature and normal pressure for 24 hours, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. This residue was purified using a silica gel column (methylene chloride:methanol = 200:1), and the eluate was concentrated under reduced pressure.The residue was dissolved in methylene chloride, and a 10% hydrochloric acid-ethyl acetate solution was added, and further concentrated under reduced pressure. Crystals were obtained. This is methanol-IPB
The title compound was recrystallized from 0.33% and had the following physical properties:
g (yield: 80%).

・Melting point (t); 224-225 ・Elemental analysis value: HN as CzsfbJO・HCI Theoretical value (%) 74.68 7.63 3.79 Actual value (%) 74.66 7,65 3.7760% hydrogenation After washing 0.32 g of sodium with hexane, T
10ml of HF was added. Add 1 diethyl into this at 0℃.
- indanon-2-ylphosphonate 2.12 g TH
30 ml of F solution was added dropwise. After stirring at room temperature for 30 minutes, the mixture was cooled again to 0°C, and a solution of 3.43 g of 1-benzyl-4-piperidine acetaldehyde in 10 ml of DMF was added. After heating and refluxing at room temperature for 2 hours, at 50°C for 2 hours, and for further 2 hours, methanol and 20% sulfuric acid were added at 0°C. After 10 minutes, the mixture was made basic with an aqueous solution of saturated hydroxide) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified using a silica gel column (methylene chloride:methanol = 500:1). After concentrating the eluate under reduced pressure, the residue was dissolved in methylene chloride, 10% hydrochloric acid-ethyl acetate solution was added, and the title compound was concentrated under reduced pressure.
．． 78 g (yield 27%) was obtained. Additionally, 1.37 g of diethyl 1-indanon-2-ylphosphonate was recovered.

・Molecular formula; C, 3825NG・IIcI・'H-NM
R (CDCI,) δ; 1.10-2.13 (7H,
m), 2.26 (2H, t), 2.88 (2H, bd
), 3.48 (2t(,s), 6672-7.07
(2H, m), 7.30 (5H, s>, 7.10~
8.00 (5H, m) Synthesis of dehyde 26.0 g of methoxymethylenetriphenylphosphonium chloride was suspended in 200 ml of anhydrous ether,
．． A 6M n-butyllithium hexane solution was added dropwise at room temperature. After stirring at room temperature for 30 minutes, cooled to 0°C,
A solution of 14.35 g of 1-benzyl-4-piperidone in 3Qml of anhydrous ether was added.

After stirring at room temperature for 3 hours, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. This was dissolved in ether and extracted with 1N hydrochloric acid. Further, the pH was adjusted to 12 with an aqueous sodium hydroxide solution, and then extracted with methylene chloride. After drying over magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was purified using a silica gel column to obtain 5.50 g (yield: 33%) of an oily substance.

Dissolve this in 40 ml of methanol and 40 ml of IN hydrochloric acid.
added. After heating under reflux for 3 hours, the mixture was concentrated under reduced pressure, and the residue was dissolved in water and oxidized with condensed water.The pH was adjusted to 12 with an aqueous IJ solution, and the mixture was extracted with methylene chloride. After washing with saturated brine, drying over magnesium sulfate, and concentrating under reduced pressure, the resulting residue was purified using a silica gel column to obtain the title compound 2.7.
7 g (yield 54%) was obtained as an oily substance.

・Molecular formula: C+J+JO = HNMR (CDCI, l) δ; 1.40-2.40
(7H, m), 2.78(2)t, dt), 3.4
5 (2H, s), 7.20 (5H, s), 9, 51 (
IH, d) This reaction was carried out under an argon atmosphere.

2.0 diisopropylamine in 10 ml of m water THF
Then, 9.12 ml of 1.6M n-butyllithium hexane solution was added at 0°C. 10 at 0℃
After stirring for several minutes, it was cooled to -78°C, and 2.55 g of 5,6-dimethoxy-l-indanone was added to anhydrous T)IP 30.
m1 solution and hexamethylphosphoramide 2.311Tl
] was added. After stirring at -78°C for 15 minutes, 1-benzyl-4-piperidinecarbaldehyde 2 obtained in (a)
, 70 g of anhydrous THF in 30 ml was added. After gradually raising the temperature to room temperature and further stirring at room temperature for 2 hours,
A 1% aqueous ammonium chloride solution was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying with magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column (methylene chloride:methanol = 500:1 to 100:1).
). After the eluate was concentrated under reduced pressure, the residue was dissolved in methylene chloride, a 10% hydrochloric acid-ethyl acetate solution was added, and the mixture was further concentrated under reduced pressure to obtain crystals. This was recrystallized from methylene chloride-IPE to obtain 3.40 g (yield: 62%) of the title compound having the following physical properties.

・Melting point (t): 237-238 (decomposition) ・Elemental analysis value: CHN as C24H2JO3・HCI Theoretical value (%) 69.64 6,82 3.38 Actual value (
%) 69.51 6.78 3.30 Hydrochloride 1-benzyl-4-[: (5,6-ditytoxy 1-
indanone)-2-ylidenyl]methylpiperidine 0.
40 g was dissolved in 15 ml of THF, and 0.04 g of 10% haladium-carbon was added. After hydrogenation at room temperature and normal pressure for 6 hours, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. This residue was purified using a silica gel column (methylene chloride: methanol = 50:1), and the eluate was condensed under reduced pressure.The residue was dissolved in methylene chloride, 10% hydrochloric acid-ethyl acetate solution was added, and the mixture was further concentrated under reduced pressure. and obtained crystals. This was recrystallized from ethanol-IPB to obtain 6 g (yield: 82%) of the title compound OJ having the following physical properties.

・Melting point (t); 211-212 (decomposition) ・Elemental analysis value: HN as C24H29NO3・HCI Theoretical value (%) 69.30 7.27 3.37 Actual value (%) 69.33 7.15 3.22g , 4-
40 g of (2-aminoethyl)benzylpiperazine is stirred at 200° C. for 7 hours in a shielded tube. after that,
The product was purified using a silica gel column and converted into a hydrochloride by a conventional method to obtain 6.37 g of the dihydrochloride of the target product.

・Melting point (t): 143.5-145 ・Elemental analysis value:
HN as C21H2SN30・2HC1 Theoretical value (%) 61.77 6.66 10.29
Actual value (%) 61.49 6.68 9.982
-Hydroxymethylnicotinic acid lactone 12.62.3
-dihydro-5,6-simethoxyoxyvirolo(3,4
-b] Benzene 0.5 g Dissolve in DMF together with potassium iodide of gold catalyst 1. While cooling and stirring, 0.21 g of sodium hydride (60%) is added.

Then, 1 g of 2,3-dihydro-5゜6-simethoxyoxypyrrolo(3,4-b)benzene was added, and the
Stir for an hour. After completion, add lI20, extract with chloroform, wash the chloroform layer with water, dry (MgSO,),
The solvent is distilled off and purified on silica gel to obtain the desired oil.

Approximately 0.2 g of cream-colored crystals were obtained by converting this into a hydrochloride salt using a conventional method.

・Molecular formula: C24H:+oN203'28C1・'
H-NMR (CDCl2) δ; 1.12-3.4 (
9H, m), 2.72-3.00 (2H, m).

3.48 (2H, s>, 3.62 (2H, t), 3
．． 95 (6H, s).

4.26 (2H, s), 6.90 (LH, s), 7
．． 28 (6H, s> Under a nitrogen stream, 30 g of 2-nitrobenzaldehyde, 21.4 g of 1-benzyl-4-aminoethylpiperidine, 100 ml of methanol are stirred at room temperature for 3 hours.

The reaction solution was cooled on ice, and 16 g of sodium borohydride was added to the Mo
Add 30 ml of O3 solution dropwise. After further reacting at room temperature for 1 hour, it was poured into water and extracted with methyl chloride.
Extract three times with 150 ml of 0% hydrochloric acid and wash with methylene chloride. This aqueous layer was adjusted to pH 10 with sodium carbonate, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
N-(.

28.4 g of -nitrobenzyl)ethylcopiperidine are obtained.

This was dissolved in 100 ml of methanol and hydrogenated using 3 g of 10% palladium-carbon (hydrated) at a pressure of 4 kg/cm2 to obtain 25.6 g of the title compound.

・Molecular formula: C2182J3 ・IH-NMR (CDC13) δ; 1.0 to 2.1 (9
H, m), 2.64 (2) 1. t), 2.90 (2
H, m), 3.47 (2H, s), 6.65 (2H,
m), 7.02 (2H, m), 7.30 (5H, s
) Example 8 Example 9 25.6 g of 4-CN-(o-aminobenzyl)ethyl]-1-benzylpiperidine, 15 g of 1,1'-carbonyldiimidazole, 100 ml of methanol were heated under reflux for 12 hours. After the reaction, the water is removed, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

This residue was purified by silica gel column chromatography (5% Meal (C) + 2c12) and recrystallized twice from ethyl acetate to obtain 3.0 g of the title compound.

・Molecular formula; C2J2JsO ・'H-NMR (CDCI,) δ; 1.0-2.1 (9
H, m), 2.7~3.0 (2H, m), 3.2~
3.6 (4H, m), 4.4 (2H, s), 6.5~
7.4 (8H, m), 7.75 (LH, s) hydrochloride CH.

Suspend 0.35 g of sodium hydride in 0.5 ml of dimethylformamide (DMF), stir under water cooling, and add 1.2.3.4-tetrahydro-4-methyl-58-1,4-benzdiazepine. -2-on 0,5
Dissolve 2 g in 3 ml of DiAF, add dropwise, and stir at room temperature.
Stir for 0 minutes. Add 0.111g of N-benzyl-4-(2-chloroethyl)piperidine hydrochloride to this in 3ml of DMF.
1 and added dropwise, and stirred at 60-70°C for 7 hours.

Pour into ice water and extract with methylene chloride.

Wash with saturated saline and dry with magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography, followed by a hydrochloride salt using a conventional method.

0.17 g of pale yellow amorphous material is obtained (yield 13.5%).

・Molecular formula; C24H3□N, 0.28C1.'H-NM
R(CDCI3)δ; 1.25-2.02 (9H,
m), 2.52 (3H, S), 2.79-2.95 (2
H, bd), 3.10 (2H.

S), 3.48(2H,s), 3.54(2t(,s
), 3.91 (2H.

bt), 7.14-7.45 (9H, m), dissolved in 4rnl and added dropwise. After heating at 60°C for 15 minutes, cool on ice,
Add 1.02 g of N-benzyl-4-(2-chloroethyl)piperidine hydrochloride, and then stir at 60°C for 3 hours.
Stir for 1 minute. After cooling, pour into ice water and extract with methylene chloride. After washing with water, it is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.

After purification by silica gel chromatography, it is converted into a hydrochloride salt using a conventional method to obtain 1.40 g of the title compound (yield 94.8%).

・Molecular formula: C24H3(lN20 ・HCI・'H-
NMR (CDCI,) δ: 1.20-1.92 (IIH
, m) , 2.20-2.24 (4H, bs) , 2
．． 60-2.88 (4H, m), 3.44 (2H, s
), 7°12-7.24 (9H, m) 0.27 g of sodium hydride was dissolved in dimethylformamide (DMF
) Suspend in 0.5 ml and stir under water cooling. 1 for this
．． 2.3.4-tetrahydro-5day-1-penzazepin-2-one 0.60 g in DMF5, 6.11.1
Put 2.24 g of 2-tetrahydrobenzo (b, f2 azomin-6-one and 60% sodium hydride in 20 ml of dimethylformamide, heat and stir at 60°C for 1 hour, and then add 1-benzyl-4-chloroethylpiperidine ,7g
Add 3. Milk time reacts.

The reaction solution was poured into 2 Qml of water, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (5
%MeOHin CLC12) Purification and separation to obtain 0.6 g of the title compound.

・Molecular formula; CzstbJ20・HCl-'H-NMR
(CDCI,) δ; 1.1-2.2 (9H, m), 3
．． 7-4.1 (4H, m), 4.15-4.5 (2H
, m), 4.46(2)1. s), 6.8-7.4
0.25 g of (13H, m) acid salt sodium hydride is suspended in dimethylformamide (DMF) and stirred under water cooling.

Here, 10.11-Sibidero-5-methyl-5H-
Dibenzo[b,e](1,4]-diazepine-1i-one is dissolved in 10.58gfi-DMF 5rnl and added dropwise. Stirred at 40-50°C for 20 minutes, then cooled on ice, and added 4-(aminoethyl )-1-benzylpiperidine 0.
Add 71 g and stir at 45-55°C for 6 hours. Pour into ice water and extract with methylene chloride. After washing the organic layer with saturated brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with a silica gel column to obtain 0.78 g of the title compound as a hydrochloride as a pale yellow amorphous substance (yield 65.4%). Molecular formula: Czslb+LO・HCI・IH-NMR
(CDC13) δ; 1.20-1.91 (IIH,
m), 2, 60-3.00 (2H, bs), 3
．． 22 (3H, s), 3.41 (2H, s), 6.87
~7.08 (3H, m), 7.08 (9H, m),
7,64 (IH, dd) Add. This is washed with a saturated aqueous potassium carbonate solution and brine, dried, and then the solvent is distilled off. Further purification was performed using a silica gel column, and the obtained crystals were recrystallized from ether-hexane to obtain 8.81 g of white crystals, which were the desired product. This was made into a hydrochloride by a conventional method.

・Elemental analysis value: CzsH3oN*Os ・)ICI ・
HN theoretical value (%”) 60.58 7.07 12.2
9 Actual value (%) 60.54 7.00 12.2
92. 18 g of 3-pyrazinecarboxylic anhydride was added to 200 ml of isopropyl alcohol and refluxed for 1 hour. Thereafter, the alcohol was distilled off, and the resulting solid was dissolved in THF to give 30% of 4-(2-aminoethyl)benzylpiperidine.
6 g and 21 g of 1-hydroxybenzotriazole are added. Stir the mixture under cooling, add 29.7 g of DCC,
Let react overnight at room temperature. After filtration, THF was distilled off and methylene chloride was extracted with 2g of 2-quinoxalinecarboxylic acid chloride.
In the presence of 2.52 g of 1-(p-methoxybenzyl)-4-piperidineethylamine and 2 g of triethylamine,
The reaction was carried out in THF at room temperature. By post-treating and column purifying this by a conventional method, N-[4°-(1″-(
p-methoxybenzyl) piperidine) ethyl]-2-
2.5 g of quinoxaline carboxylic acid amide was obtained.

This was dissolved in 1 g of methylene chloride and demethylated with BBr3, followed by column purification to produce a product of 0,
3g was obtained. By converting this into a hydrochloride, 0.2 g of cream-colored crystals was obtained.

・Molecular formula; C2J2sN<02・HCI・')IN
MR (CDCI,) δ; 1.08-1.92 (9H
, m), 2.84-3.18 (2H, m), 3.24
~3.64 (2H, m), 3.52 (2H, s), 6.
60 (2H, d), 7.05 (2H, d), 7.1
7 (2H, s), 7.64-8.14 (4H, [11>
, 9.53 (IH, m) 4.6 g of -benzyl-4-aminoethylpiperidine, 50 ml of pyridine 1. 4-Dimethylaminopyridine was added at room temperature with stirring, and 40 g of 2-quinoxaloyl chloride was added. After reacting for 3 hours, the mixture was poured into water, extracted with methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

This residue was purified by silica gel column chromatography (5% IJe[lHCH2Cl2) and recrystallized from ethyl acetate to obtain 3.0 g of the title compound.

・Molecular formula: Cz3HzNaO□・HCI・'HNP
JR (CDC13) δ: 1.16-2.20 (9H
, m), 2.76-3.04 (2H, m), 3.49
(2ft, s), 3.48-3.68 (2H, t)
, 7.13~7.40 (5N, m), 7.70~8
．． 26 (4H, m), 9.64 (IH, 5) ~2-quinoxalinecarboxylic acid amide 4-(N-benzoylpiperidyl)acetic acid 47 g, thionyl chloride 8 ml and benzene 20 ml After heating under reflux for 2 hours,
Distill under reduced pressure.

This was dissolved in 20 ml of THF, and while stirring under water cooling, 1.86 g of aniline, 10 g of ethylamine, TH
Add dropwise into 30ml of F. After reacting at room temperature for about 11 hours, the mixture was poured into water and extracted with methylene chloride. Wash with saturated brine, dry over anhydrous magnesium sulfate, and evaporate under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH + n CH2Cl2).
0.9 g of benzoylpiperidyl)acetic acid anilide is obtained.

This 4-(N-benzoylpiperidyl)acetic acid anilide 0
．． 9 g was dissolved in 10 ml of THF, and while stirring under water cooling, THF
F Lithium aluminum hydride 0 in 30m1,
38 g was added dropwise, and the mixture was further heated under reflux for 1 hour.

After the reaction, water was added, the precipitate was filtered off, and extracted with ethyl acetate.
Washed with saturated saline, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 0.7 g of 1-benzyl-4-(N'-phenylaminoethyl)piperidine.

・Molecular formula; C2oHzsN2-'H-NMR (CDC13) δ; 1.0-2.2 (
9H, m), 2.85 (2H, m), 3.10 (2
H, t), 3.44 (2H, s), 3.7 (LH, b
s), 6.4-6.8 (3H, m), 7.0-7.
4(78,m>■-benzy-4-(N'-phenylaminoethyl)piperidine 0.7 g, ) IJ ethylamine 2.
0g of THF, 0.4g of acetyl chloride was added dropwise to the mixture while stirring under water cooling.

After reacting for 3 hours at room temperature, 2Q+nl of water was added, extracted with methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (5% MeOHin C) +
2c12) L, the title compound is obtained.

・Molecular formula: C25HzsN20 ・'H-NMR (CDC13) δ; 1.
O~2.1 (12H, m), 2.6~3.0 (2
N, m), 3.39 (2H, s), 3.67 (2
H,t), 6,9-7.5 (IOH,m), washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

This residue is purified by silica gel column chromatography (5% MeOHin CH2Cl2).

0.9 g of the title compound was obtained as a hydrochloride by a conventional method.

・Molecular formula; C,,83SN203F -HCI・'1
1-NMR (CDC'l,) δ; 1.1-2.1 (9H
, m), 2.7-3.0 (2H, bd), 3.5
1 (2H, s), 3.83 (8H, m), 6.1-6
．． 4 (4H, m>, 6.9-7.8 (10H, m)
1.0 g of 1-benzyl-4-(N'-(3°,5'-dimethoxyphenyl)aminoethylcopiperidine.

2.0 g of triethylamine and 20 ml of THF were stirred with water cooling, and 0.51 g of p-fluorocinnamic acid chloride was added.
Add. Pour into reaction condensate for 2 hours at room temperature, add ethyl acetate N-
Dissolve 0.70 g of (4'(1'-benzylpiperidine)ethyl)aniline and a catalytic amount of 4-(N,N''-dimethylamino)pyridine in 30 ml of pyridine and stir under water cooling.Here, isonicotinic acid chloride hydrochloric acid salt 0.8
Add 5 g and stir for 3 hours and 30 minutes.

The solvent is distilled off under reduced pressure, and the residue is purified using a silica gel column. Dihydrochloride was obtained using a conventional method, and the result was 0.75 as a pale yellow amorphous substance.
g (yield 73.0%)・Molecular formula; C26H29
N30・211CI・'It-NMR (CDCI,) δ
; 1.13-2. Oh! E, m), 2.81 (2
H, bd), 3.44 (2H, s), 3.88 (2
H, bt), 6.84-7.26 (12H, m), 8
．． 31 (2H, d) Dry over MgSO. The solvent was distilled off again and the product was purified using a silica gel column to obtain the desired oil. Furthermore, 0.14 g of white crystals was obtained by converting this product into a hydrochloride according to a conventional method.

・Melting point (t); 197.5-198 ・Elemental analysis value:
C21826N20 HN as HCI Theoretical value (%) 70.28 7.58 7.81 Actual value (%) 70.50 7.58 7.83 Lido hydrochloride Aniline 0.5 g,) Lithylamine 1 g in THF dissolve. 1 g of 4-(1-benzylpiperidine)propionic acid chloride was added dropwise to this solution while stirring, and
Allow time to react. After that, the solvent was distilled off, methylene chloride was added, washed with water, 0.74 g of benzyl chloride, 3-
1 g of (2°-aminomethyl)-benzylpyrrolidine was stirred and reacted at room temperature in THF in the presence of 1.5 g of triethylamine. This was post-treated and column purified using a conventional method to obtain 0.32 g of the target product. This was converted into the hydrochloride salt by a numerical method.

・Molecular formula; C1982□N20・HCI・'H-NM
R(CDC13)δ; 1, 48-3.08 (7H, m), 3.44 (2H
, d), 3.62 (2H, d), 7.04-7.88
(IOH, m) Stir for 10 minutes. Add a 1% aqueous ammonium chloride solution, extract with methylene chloride, wash with saturated brine, dry over anhydrous magnesium sulfate, and evaporate under reduced pressure. The residue is purified by silica gel column chromatography (5% MeOHCH2Cl2) to give 2.0 g of the title compound.

・Molecular formula: C23H29NO3 −' H-NMR (CDC1,) δ ; 1.0 ~
2.2 (98, m), 2.6-3.4 (5H,
m), 3.43 (2H, s), 3.81 (3H, S
), 4.1 (11(), 6.83 (2H, d), 7.
17 (5H,s), 7,82 (2H,d) Under a nitrogen stream, add 2ml of diisopropylamine to 7ml of TflF, add 7.5ml of 1,6M n-butyllithium hexane solution at 0°C, and stir for 10 minutes. After, -7
Cool to 8℃ and p-methoxyacetophenone 1.65
Add a solution of 10 g of THF in 10 ml and stir for 20 minutes. Furthermore, 1-benzyl-4-piperidinecarbaldehyde 2
．． Add 4 g of THF in 10 ml and add 4-[4'(N-benzyl)piperidyl)-3-hydroxy p-methoxybutyrophenone 0 using a Dean-Stark apparatus.
．． 54g, p-toluenesulfonic acid 0.1g, )
Heat and reflux with 3 Qml of toluene for 5 hours. After the reaction, it was poured into an aqueous potassium carbonate solution and extracted with methylene chloride.
Dry over anhydrous magnesium sulfate and evaporate under reduced pressure. The residue was purified by column chromatography (3% MeOHCH2
C12) L, 1-benzyl-1-[4-(p-methoxyphenyl)-4-oxobutylcopiperidine 0.45
get g. Dissolve this in 820 ml of MeO and add 10%
Add 40 mg of palladium-carbon (hydrated). Hydrogenate at room temperature and normal pressure for 1.5 hours. Insoluble matter was filtered off and evaporated under reduced pressure. Hydrochloride was obtained by a conventional method, and Me[]H-IPIE
Crystallization yields 0.2 g of the title compound.

・Molecular formula; C2□H29NO□・HCl-')l-Nl
, IR(CDC13)δ; 1.4-2.3 (IIH
, m), 2.4-2.7 (2H, m), 2.95 (2
H,t), 3.55 (2H,s), 3,87 (3)
1. s), 6.93 (2H, d), 7.1-7.5
(5H.

m), 7.94 (2)1. d) N-[4'-(1°-benzylpiperidine)ethyl]4
- (2-aminoethyl)-1-benzylpiperidine 1
．． 64 g of potassium carbonate and 2.67 g of potassium carbonate were added to a mixture of 40 ml of chloroform and 40 ml of water, and the mixture was stirred for 1 hour under water cooling. The organic layer is separated, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, purified using a silica gel column, and converted to hydrochloride using a conventional method to obtain 1.60 g of the title compound as a pale yellow amorphous substance (yield 61.1%). Molecular formula: C19H24N20□・HCI・' H-N
MR (CDC13) δ; 1.47-2.10 (9H
, m), 2.81 (2H, bd), 3.25-3.4
7 (4H, m>, 5.80 (IH.

bs), 6.5HIH, dd), 7.15-7.1
9(6H,m),7,82 (LH,dd) N-[4'-(1'-benzylpiperidine)ethyl] Example 26 Benzamide N-(1-radamantanemethyl) -4-(2- (aminoethyl)piperidine 1.47 g, potassium carbonate 0.
Add 73 g to a mixed solution of 15 ml of chloroform and 15 ml of water, and stir vigorously while cooling with water. 0.90 g of benzoyl chloride was added dropwise thereto, and the mixture was stirred at room temperature overnight. The organic layer is separated, washed with water and saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification with a silica gel column and recrystallization from benzene-η-hexane gave 1.47 g of the title compound as pale yellow plate crystals (yield 72
．． 6%).

・Molecular formula: C25H+6NzO ・'H-NMR(-CDC1,)δ; 1.29-2
．． 28 (27N, m) 2.72 (2H, bs),
3.43 (2H, q), 6.01 (IH, bs), 7
, 31-7.43 (3H, m), 7.67 (IH,
dd) 0.18 g of sodium hydride is suspended in 2 ml of tetrahydrofuran (THF) and stirred under water cooling. Here, 1.45 g of N-[4°-(1′-benzylpiperidine)ethyl]benzamide was added to TI(F
Add 5ml of the solution dropwise. After stirring at room temperature for 1 hour, the mixture was cooled on ice again, and 0.36 ml of methyl iodide was added.
- Stir overnight at room temperature. Pour into ice water, extract with chloroform under salting out, wash with saturated saline, and dry over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography. 0.60 g of yellow oil is obtained (yield 47
．． 0%).

In addition, 0.22 g of unmethylated raw material was recovered (recovery rate 15.2%). The obtained oil was converted into a hydrochloride salt in a conventional manner to obtain 0.52 g of the title compound as a yellow amorphous substance (yield 37.6%).

・Molecular formula; C25H3eN20・HCl・'HN! J
R(CDC1a)δ; 0.92-3.60 (63)
1. m), 7,29 (5)1.5) CH2CI2)-L, 0.3 g of the title compound is obtained.

・Molecular formula; C2□H34N20・HCI・'H-NMR
(('DC1,) δ; 0.8 to 1.6 (4H, m),
1.8 (5H,s) ~1.1 (20H,m), 1.1 ~2.6 (5H,m>,7.4l)ethyl]N-methylbenzamide/hydrochloride indanone)-2- Il2methylpiperidiN-methyl-N-(
4'-piperidylethyl)benzamide 0.6 g, cyclohexyl bromide 1.2 g, sodium hydrogen carbonate 2
．． 0 g of methyl ethyl ketone and 39 ml of methyl ethyl ketone were heated under reflux for 7 hours. After the reaction, it is added to water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. This residue was purified by silica gel column chromatography (5% M e O). 0.85 g of 1-5,6-simethoxy-1-indanone and 1.38 g of 1-benzoyl-4-piperidine-carbaldehyde were dissolved in 20 ml of anhydrous THF. , 1.02 g of 28% sodium methylate was added at 0°C. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed with saturated brine. After drying over magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was purified using a silica gel column to obtain 1-penzoyl-4-((5,6-simethoxy-1-indanone)-
2-ylidenyl]methylpiperidine 1.23 g (yield 7
1%).

Dissolve 1.23 g of this compound in 20 ml of THF,
0.3 g of 10% palladium-carbon was added. After hydrogenation for one day at room temperature and normal pressure, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. This was recrystallized from methylene chloride-hexane,
1.10 g (yield 89%) of the title compound having the following physical properties
I got it.

・Melting point (t); 151-152 ・Elemental analysis value: HN as C24H27NO4 Theoretical value (%) ? 3.26 6.92 3.56 Actual value (%) 73.30 6.85 3.32 1-benzoyl-4-[:(5,6-simethoxy1-indanone)-2-ylcomethylpiperidine 9.00 g was dissolved in 99 ml of dioxane, and 90 ml of 6N hydrochloric acid was added.

After heating under reflux for 10 hours, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate.

The aqueous layer was adjusted to pH 12 with a 50% aqueous sodium hydroxide solution, extracted with methylene chloride, and further washed with saturated brine. After drying with magnesium sulfate, concentrate under reduced pressure,
The obtained residue was converted into a hydrochloride salt by a conventional method and recrystallized from methanol-ether to obtain the title compound 6 having the following physical properties.
JOg (yield 85%) was obtained.

・Melting point (t); 249-250<decomposition) ・Elemental analysis value: C+J2JOs・HN as HCI Theoretical value (%) 62.67? , 42 4.30 Actual value (%) 62.75 7.31 4.52 Tylpiperidine hydrochloride Example 31 4-[:(5,6-Simethoxy 1-indanone) 2-
0.25 g of ylcomethylpiperidine was dissolved in 6 ml of THF, and 0.29 ml of triethylamine and 0.13 ml of 3-fluorobenzylbromide were added. After heating under reflux for 2 hours, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with a 10% aqueous sodium carbonate solution and saturated brine. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was purified using a silica gel column. Furthermore, it was converted into a hydrochloride salt by a conventional method and recrystallized from methylene chloride-IPE to obtain 0.27 g (yield 72%) of the title compound having the following physical properties.

・Melting point (t); 230-232 (decomposition) ・Elemental analysis value; HN as C24H27NO4・HCI Theoretical value (%) 66.43 6.74 3.23 Actual value (%) 66.18 6.79 3.112 Hydrochloride 5.6-Simethoxy 1-indanone 1.00 g.

0.31 g of paraformaldehyde and 0.99 ml of 1-benzylpiperazine were suspended in 3Q+nl of ethanol and 2 ml of water, and the pH was adjusted to 3 by adding concentrated hydrochloric acid. After heating under reflux for 3 hours, the mixture was allowed to cool and a white solid was filtered off. This was suspended in methylene chloride and washed with a 10% aqueous sodium carbonate solution and saturated brine. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was purified using a silica gel column. Furthermore, it was converted into a hydrochloride salt by a conventional method and recrystallized from methanol to obtain 0.55 g (yield 23%) of the title compound having the following physical properties.

・Melting point (t'); 227-228 (decomposition) ・Elemental analysis value; CH as CzsHxsN203/211CI
N Theoretical value (%) 60.79 6.88 6.16 Actual value (%) 60.31 6.95 6.06 Melting point (
t); 132-133 Elemental analysis value: H as C20H27NO5 Theoretical value (%') 66.46 7.53 Actual value (%)
66.79 7.53 3.88 4.00 Veridine Veridine 1-benzyl-4-((5,6-simethoxy1-indanone)-2-ylcomethylpiperidine 0.50 g
Dissolve in 8 ml of benzene and add 0.15 ethyl chloroformate.
m1 was added. After heating under reflux for 3 hours, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-hexane to obtain 0.45 g (yield: 94%) of the title compound having the following physical properties.

4-[(5,6-Simethoxy1-indanone)-2-
yl]methyl-1-ethoxylponylbiveridine2.
00 g in 30 ml of carbon tetrachloride, 0.98 g of N-bromosuccinimide and 0.02 g of benzoyl peroxide.
g was added. After heating under reflux for 5 hours, the mixture was diluted with carbon tetrachloride and washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over magnesium sulfate, it was concentrated under reduced pressure.

This residue was dissolved in 20 ml of THF, and 1,8-diazabicyclo[:5.4.01 undec-7-ene 1,65
m1 was added. After heating under reflux for 30 minutes, it was concentrated under reduced pressure.
It was diluted with ethyl acetate and washed with saturated brine. After drying over magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was purified using a silica gel column to obtain 1.12 g of the title compound (
Yield: 56%) was obtained as an oil.

・Molecular formula; C2゜LsNOs ・'H-NMR (CDC1,) δ; 1.23 (3H
, t), 1.41-2.90 (IIH, m), 3.
84<3H.

s), 3.88 (3H, s), 4.10 (2H, q
), 6.60 (IH, s).

6.97 (LH, s), 7.03 (LH, s) 0.1
Then, 0.75 ml of a 1.6M n-butyllithium hexane solution was added at 0°C. 10 at 0℃
After stirring for a minute, the mixture was cooled to -78°C, and a solution of 0.18 g of 1°3-indanedione in 8 ml of anhydrous THF and 0.21 ml of hexamethylphosphoramide were added. -78℃
After stirring for 15 minutes, a solution of 0.35 g of 1-benzyl-4-piperidinecarbaldehyde in 3 ml of anhydrous THF was added. After gradually raising the temperature to room temperature and stirring overnight at room temperature, the mixture was diluted with methylene chloride and washed with saturated brine.

After drying over magnesium sulfate, it was concentrated under reduced pressure, and the resulting residue was recrystallized from methylene chloride-IPE to obtain 0.12 g (yield 29%) of the title compound having the following physical properties.

・Melting point (t); 173-174 (decomposition) ・Elemental analysis value: CHN theoretical value (%) as C22Hz+NO□? 9.73 6.39 4.23 Actual value (%)? 9.43 6.20 4.31m water T
Diisobutyramine 1-benzyl- in 3 ml HF
4-[(5,6-simethoxyinderopyl piveridine)
2-yl]methylpiperidine hydrochloride 1-benzyl-4-((5,6-dimethoxy-1-indanol)
0.24 g of [-2-yl]methylpiperidine was dissolved in 5 ml of methylene chloride, a 10% hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The resulting residue was diluted with methylene chloride-IP.
0.2 of the title compound recrystallized from E and having the following physical properties
4 g (yield 95%) was obtained.

・Melting point (t); 216-217 (decomposition) ・Elemental analysis value: C24) 129No□・ON as HCI Theoretical value (%) 72.07 7.56 3.50 Actual value (%) 71.82 7.63 3J31-indanone)-2-ylidenyl]]-bu 31 ml of diisopropylamine Q was added to ml of anhydrous THFS, and further heated to 0°C.
1.6M n-butyllithium hexane solution at 1.39
m1 was added. After stirring at 0°C for 10 minutes, -78°C
Cool to 5° 6-Simethoxy 1-indanone 0.
A solution of 39 g in 5 ml of anhydrous THF and 0.35 ml of hexamethylphosphoramide were added. After stirring at −78° C. for 15 minutes, a solution of 0.50 g of 3-(1-benzyl-4-piperidine)propionaldehyde in 5 ml of anhydrous THF was added. Gradually raise the temperature to room temperature, and then at room temperature for 3
After stirring for an hour, the mixture was diluted with ethyl acetate and washed with saturated brine. After drying with magnesium sulfate, concentrate under reduced pressure,
The obtained residue was purified using a silica gel column and converted into a hydrochloride salt by a conventional method to obtain 0.55 g (yield 61%) of the title compound as an oily substance.

・Molecular formula: CzaL+NL・HCI ・'H-NMR (CDC13) δ; 1.10-3.
00 (13H, m), 3.45 (2) 1. s),
3.50 (2H.

s), 3.90 (3H, s), 3.95 (3H
,s), 6.58-7.20(3H,m), 7
．． 27(5)1. s).

・Molecular formula: C25H3sNO3・HCI・'H-NM
R(CDC1,) δ; 1.00 to 3.30 (18H
, m), 3.38.3.43 (total 2H.

each s), 3.85 (3H, s), 3.90
(3H,s), 6.7-7゜6.83(total
IH, each s), 7.05.7.10 (tot
alIH, each s), 7.13, 7.2Q (t
otal 5H, each s) Examples 38 to 249 Compounds synthesized in the same manner as Examples 1 to 37 are shown in Tables 5 to 1.
0.

Claims (1)

[Claims] 1 The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, J is (a) a substituted or unsubstituted group shown below; {1} phenyl group, {2} pyridyl group, {3} pyrazyl group, {4
}quinolyl group, {5} cyclohexyl group, {6} quinoxalyl group or {7} furyl group, (b) a monovalent or divalent group selected from the following group, which may be substituted with phenyl group; { 1} indanyl, {2}
Indanonyl, {3} indenyl, {4} indenonyl, {5} indanedionyl, {6} tetralonyl, {7
}Benzuzuberonil, {8} indanolyl, {9} formula▲
There are mathematical formulas, chemical formulas, tables, etc. Groups indicated by ▼, (c) Monovalent groups derived from cyclic amide compounds, (2
) lower alkyl group, or (e) a group represented by the formula R^1-CH=CH- (wherein R^1 means a hydrogen atom or a lower alkoxycarbonyl group). B is a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc.
In the formula, R^3 is a hydrogen atom, a lower alkyl group, an acyl group,
(lower alkylsulfonyl group, optionally substituted phenyl group or benzyl group), formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^4 is a hydrogen atom, lower alkyl group or There are groups, formulas (meaning phenyl group), formulas ▲ mathematical formulas, chemical formulas, tables, etc. Groups, formulas represented by ▲ there are mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ Numerical formulas, chemical formulas, tables, etc. There are groups represented by ▼ {In the above formula, n means 0 or an integer from 1 to 10. R^2 is a hydrogen atom, Means a methyl group. ), a group represented by the formula = (CH-CH=CH)_b- (in the formula, b means an integer from 1 to 3), a group represented by the formula =C
A group represented by H-(CH_2)_c- (in the formula, c means 0 or an integer from 1 to 9), formula = (CH-CH)_d
=(In the formula, d means 0 or an integer from 1 to 5) There are groups, formulas ▲ Numerical formulas, chemical formulas, tables, etc. There are groups, formulas ▼ Numerical formulas, chemical formulas, tables, etc. A group represented by the formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups represented by the formula -NH-, groups represented by the formula -O-, groups represented by the formula - It means a group represented by S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group. T means a nitrogen atom or a carbon atom. Q means a nitrogen atom, a carbon atom, or a group represented by the formula ▲There are numerical formulas, chemical formulas, tables, etc.▼. K is a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group that may be substituted with a phenyl group, a cinnamyl group that may be substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, adamantane It means a methyl group, furylmethyl group, cycloalkyl group, lower alkoxycarbonyl group or acyl group. q means an integer from 1 to 3. In the formula, ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ means a single bond or double bond. ] A therapeutic/preventive agent for diseases based on choline acetyltransferase activation, which contains a cyclic amine derivative represented by the following and a pharmacologically acceptable salt thereof as an active ingredient. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, J^1 is a monovalent or divalent group selected from the following group, which may be substituted with a phenyl group; {1} indanyl, {2
}Indanonyl, {3}indenyl, {4}indenonyl, {5}indanedionyl, {6}tetralonyl, {
7} Benzsuberonyl, {8} Indanolyl, {9} A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, a group represented by the formula ▲ Mathematical formula, There are chemical formulas, tables, etc. ▼ There are groups, formulas indicated by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (
In the formula, R^3 is a hydrogen atom, a lower alkyl group, an acyl group,
(lower alkylsulfonyl group, optionally substituted phenyl group or benzyl group), formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^4 is a hydrogen atom, lower alkyl group or There are groups, formulas (meaning phenyl group), formulas ▲ mathematical formulas, chemical formulas, tables, etc. Groups, formulas represented by ▲ there are mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ mathematical formulas, chemical formulas, tables, etc. There are groups represented by ▼, formulas ▲ mathematical formulas, chemical formulas, tables, etc. Groups represented by ▼ (In the above formula, n means 0 or an integer from 1 to 10. , tables, etc. ▼ means a hydrogen atom or a methyl group in such a form that the alkylene group has no substituent or has one or more methyl groups.), Formula A group represented by =(CH-CH=CH)_b- (wherein b means an integer of 1 to 3), formula =C
A group represented by H-(CH_2)_c- (in the formula, c means 0 or an integer from 1 to 9), formula = (CH-CH)_d
=(In the formula, d means 0 or an integer from 1 to 5) There are groups, formulas ▲ Numerical formulas, chemical formulas, tables, etc. There are groups, formulas ▼ Numerical formulas, chemical formulas, tables, etc. A group represented by the formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups represented by the formula -NH-, groups represented by the formula -O-, groups represented by the formula - It means a group represented by S-, a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group. T means a nitrogen atom or a carbon atom. Q means a nitrogen atom, a carbon atom, or a group represented by the formula ▲There are numerical formulas, chemical formulas, tables, etc.▼. K is a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group that may be substituted with a phenyl group, a cinnamyl group that may be substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, adamantane It means a methyl group, furylmethyl group, cycloalkyl group, lower alkoxycarbonyl group or acyl group. q means an integer from 1 to 3. In the formula, ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ means a single bond or double bond. ] The therapeutic/prophylactic agent according to claim 1, which contains a cyclic amine derivative represented by the following and a pharmacologically acceptable salt thereof as an active ingredient.